Emerging roles of activating transcription factor 2 in the development of breast cancer: a comprehensive review

Abstract Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins that are responsible for regulating various genes that play an essential role in major biological and cellular functions. Since ATF2 plays a vital role in cellular proliferation and apoptosis, it is believed that it greatly affects the development of breast cancers. However, its exact role in breast cancer is incompletely understood. It remains a subject of debate, ambiguity, and continuous research. Several studies have suggested the role of ATF2 as an oncogene, promoting cellular proliferation and worsening the outcome of cancers. In contrast, other studies have postulated that ATF2 plays a tumor suppressive role in estrogen receptor-positive breast cancer. The ambiguity surrounding its role in breast cancer is the reason why there is an influx of recent studies and research in this area. In this narrative review, we investigate several studies that have been published about the role of ATF2 in breast cancer. We also explore studies that have examined the association between ATF2 and endocrine therapy resistance. ATF2 has been suggested to modulate estrogen receptor (ER) expression and activity, potentially affecting tamoxifen sensitivity in breast cancer cells. Therefore, the role of ATF2 in DNA repair mechanisms and drug resistance has been deeply explored in this review. Additionally, there are numerous ongoing clinical trials exploring the effect of targeting ATF2 pathways and mechanisms on the outcome of breast cancers, some of which we have discussed. The studies and clinical trials that are being conducted to understand the multifaceted role of ATF2 and its signaling pathways may provide valuable insight for developing efficient targeted therapeutic solutions to enhance the outcomes of breast cancer and overcome endocrine resistance. We suggest further research to elucidate the dual roles of ATF2 in breast cancer and potential therapeutic therapies for its treatment.


Introduction
Breast cancer is the most diagnosed cancer in women in most countries.It is the second most common cause of death in women from cancer in the world. 1 It is an a ggr essiv e disease that usuall y e volv es silentl y.It accounts for 11.7% of cancer cases diagnosed worldwide. 2It also accounts for ∼6.6% of cancer deaths worldwide .It ma y be caused by both her editary m utations, whic h account for ∼5% to 10%, but nonhereditary causes have also been identified in se v er al studies. 3Its incidence has also shown a rise in consecutive generations. 4Due to its silent nature, it is usually discovered during screening or following an accidental finding.Earlier diagnosis usually indicates better prognosis. 5here is an increase in prevalence in countries witnessing socioeconomic gr owth, whic h can be attributed to the rise of several risk factors, including nulliparity and delay in childbearing a ge, or al contr ace pti v e use, hormone r eplacement ther a py, and increase in average weight and fat distribution.The decrease in postmenopausal hormonal exposure ma y ha ve led to a reduction in breast cancer cases in de v eloped countries . 2 T he occurr ence of br east cancer in men is r ar e ( ∼1% of cancers in men and 1% of breast cancer cases are men ) . 6In this r e vie w, we will discuss endocrine treatment of breast cancers and the r ole of activ ating tr anscription factor 2 ( ATF2 ) in cancer and its treatment.
Typicall y, endocrine ther a py in breast cancer is indicated for hormone rece ptor-positi ve cancer.This aids in reducing recurr ence specificall y in node-positiv e disease. 7,8Using tamoxifen as a treatment lo w ers the mortality rate of breast cancer with an absolute risk reduction of 9.2% in 15 years and an number needed to treat ( NNT ) of 11. 7,9 Five years of adjuvant tamoxifen has demonstr ated a r educed risk of cancer r ecurr ence by ∼50% in 0 to 4 years. 9,10Combined induction of both endocrine ther a py and c hemother a py may help r eac h optim um r esults. 9,10P atients who are < 35 years old or r eceiv e c hemother a py in an adjuv ant setting r eceiv e the same endocrine ther a py r egimen plus added ov arian suppr ession, whic h could be either chemical or surgical. 11istoricall y, cancer genes wer e classed as tumor suppressors or oncogenes.Ne v ertheless, it has been evident from research in the last decade that genes may behave in both ways according to the cell type and stimulus. 12One of these genes is ATF2, a member of activ ator pr otein 1 ( AP-1 ) . 13It is found on c hr omosome 2q32.When translated, it gives a large protein with 505 amino acids. 14t stimulates transcription by binding to cyclic AMP-response elements ( CREs ) and then forming a homodimer or heterodimer with c-Jun. 15Other domains include the N-terminal tr ansactiv ation domain, the zinc finger, basic leucine-zipper ( bZIP ) domain, and nuclear localization and export signals.Roles of ATF2 also include working as an epigenetic r egulator thr ough acetylation of histones H2B and H4 via a histone acetyltr ansfer ase domain.The r ole of ATF2 in suppressing or promoting tumor aggressiveness depends on subcellular localization. 16It also plays a role in the transformation of epithelial cells into highl y migr ating mesenc hymal cells in cases of cellular str ess, whic h pr omotes tumor a ggr essiv eness. 17,18ts role is not only recognized and studied in breast cancer.For instance, it has been shown that ATF2 knoc k out might lead to tumor suppression or promotion depending on the model of mice used in the experiment. 19Its roles also include the regulation of se v er al genes r esponsible for cell m ultiplication, a poptosis, tr ansformation, and inflammation. 16These genes include MMP-2 and MMP-9 in MCF10A breast epithelial cells, in which ATF2 induces their migration and promotes their in vasiveness .

Regulation of ATF2 expression and activity by phosphorylation
ATF2 belongs to the ATF and cAMP response element binding protein ( CREB ) group of bZIP transcription factors.It is also a member of the leucine zipper family of DNA binding proteins. 20hese pr oteins ar e r esponsible for r egulating numer ous genes that play vital roles in cell gr owth, pr olifer ation, cell death, inflammation, and DNA damage repair . 21A TF2 controls gene transcription as a homodimer, but it also operates as a heterodimer with other ATF and AP-1 family members. 22The attachment of these homo-and hetero-dimers to ATF/CRE causes changes that influence c hr omatin r emodelling, tr anscription, and the DNA damage response . 20T he attachment is dependent on the binding partner of ATF2. 16It can bind to CRE consensus sequences ( 5-TGACGTCA-3 ) or to AP-1 consensus sequences ( 5-TGA CTCA-3 ) . 22For the transcriptional properties of AFT2 to be activated, some phosphorylation e v ents need to occur and ar e usuall y in r esponse to extr acellular str esses suc h as hypoxia, r eactiv e oxygen species, inflammatory cytokines , ultra violet, and increased osmolarity. 23he activation domain needs to be phosphorylated, particularly the two threonine residues ( Thr69 and Thr71 ) . 24There are several phosphorylating factors that target specific ATF2 phosphorylation sites. 20For instance, p38 mitogen-activated protein kinase ( MAPK ) and c-JUN N-terminal kinase ( JNK ) ar e r esponsible for phosphorylating both Thr69 and Thr71.Ho w e v er, Epidermal gr owth factor phosphorylates only Thr71 via extracellular signal-regulated kinase ( ERK ) 1/2 ( Fig. 1 ) . 25 Se v er al articles hav e also r eported that additional signaling pathways can play a role in the phosphorylation of AFT2, such as its activation by human v accinia-r elated kinase 1 ( VRK1 ) at two sites, Ser62 and Thr73, in its activation domain, as shown in Fig. 2 . 16,26Protein kinase C also plays a role as it phosphorylates sites such as Ser121, Ser340, and Ser367. 20n addition, AFT2 is also activated by growth factors via guanine nucleotide dissociation stimulator RalGDS, the Ras/ERK pathway, and Src. 27Finally, Ser490 and Ser498 are phosphorylated by ataxia telangiectasia m utated ( ATM ) pr otein kinase. 20It is belie v ed that this is vital for intr a-S-phase c hec kpoint activ ation following ionizing r adiation.ATM pr otein kinase dir ects its localization into DNA r epair foci, wher e it colocalizes with DNA r epair mac hinery  components such as Rad50, Nbs1, and Mre11. 22The recruitment of ATF2 to irr adiation-induced foci, irr espectiv e of its tr anscription-activ ating ca pabilities , suggests that it ma y pla y a role as a sensor/adaptor early in the DNA damage response. 28ompared to wild-type ATF2 mice, genetically engineered mice with mutant ATM phosphoacceptor sites demonstrated enhanced susceptibility to ionizing r adiation.Furthermor e, these ATF2 m utant animals had an increased frequency of spontaneous and c hemicall y driv en tumor formation, indicating the r ele v ance of ATF2 phosphorylation by ATM in the acute cellular response to DNA damage and genomic stability maintenance.

ATF2 in human cancers
In this r e vie w, we will focus on the role of ATF2 in the development of breast cancer.Ho w ever , A TF2 is also involved in the tumorigenesis of se v er al other cancers , including skin cancers , leukemia, r enal cell carcinoma, br ain tumors, and cervical cancer ( Table 1 ) .
As mentioned pr e viousl y, ATF2 may also act as a tumor suppressor when activated.ATF2 plays a major role in the breakdown of the extracellular matrix by regulating matrix metalloproteases ( MMPs ) .MMP-3 is specifically found in dermal fibroblasts and is induced by interleukin 1 β ( IL-1 β) .This process is performed by activation of the ERK1/ATF2 axis .Hence , ATF2 ma y be implicated in the de v elopment of disease and conditions related to MMP-3 ov er expr ession, suc h as skin a ging, arthritis, v ascular diseases, and neur odegener ativ e diseases. 29In addition, it is implicated in se v er al cancers, suc h as br east, color ectal, lung, and pancr eatic cancer.It was also found in recent studies, including a 2022 study by Deng et al., that MMP-3 blockade inhibited cancer pr ogr ession in cellular and animal models with pancreatic ductal carcinoma.
It also reduced the rates of resistance to therap y b y gemcitabine. 30n addition, Gonzalez-Avila et al. studied the effect of MMPs in lung adenocarcinoma and showed a positive correlation between MMP-3 ov er expr ession and cancer a ggr essiv eness .T hey also concluded that they might be a potential target for future therapeutic strategies. 31,32Wen et al. also found that MMP-3 may also be implicated in colorectal cancer invasion and metastasis .T hey found that HDAC11, which downregulates MMP-3, was underexpressed in patients with colorectal cancer. 33or eov er , A TF2 was shown to induce cancer genesis and progression in T-cell acute lymphoblastic leukemia ( T-ALL ) .This is because ATF2 is one of the downstream effectors in the MAP2K7 pathw ay, as sho wn in Fig. 3 , which w as implicated in the promotion of T-ALL.It was also shown that in mouse models, inhibition of this cascade may help limit the pr ogr ession of leuk emia. 34Another stud y has shown the ov er expr ession of ATF2 in renal cell carcinoma.ATF2 leads to cell survival and c hemor esistance in cancerous cells .T he authors of the study were able to make cells more chemosensitive after targeting miR-451 to reduce ATF2.They concluded that this method might be beneficial to enhance chemosensitivity, leading to better chemotherapy outcomes in patients with renal cell carcinoma. 35ATF2 has also been studied in melanoma.Lau et al. have found evidence that demonstrates the control of migratory and invasive behaviors of melanoma by ATF2.They found that ATF2 activation via protein kinase C ε ( PKC ε ) phosphorylation ma y ha v e led to mor e adv anced and metastatic forms of melanoma.Increased PKC ε and ATF2 expression was correlated with increased cell adhesion and cell motility and decreased cell protein fucosylation.The restoration of fucosylation in mouse models also sho w ed a reduction in distant metastasis. 36TF2 may also be pr otectiv e. Nov el ther a pies ar e being de v eloped in which ATF2 is used to induce apoptosis and reduce BRAF inhibitor resistance rates, leading to an increase in apoptosis of melanoma cells.37 In addition, Gozdecka et al. identified ATF2 as a downstr eam tar get of JNK, a pr otein kinase with roles in the regulation of cell gr owth, differ entiation, and a poptosis .T hey found that this pathway may play an important role in the suppression of tumor formation in the liver and ma y pro vide a potential strategy to treat liver cancer.38

Role of ATF2 in breast cancer
Despite all the studies, the definite role of ATF2 in breast cancer is still ambiguous, but r esearc h suggests that it may act as an oncogene. 22We will delve deeper into some studies done on the topic to give us a clearer picture of the evidence at hand.A study performed by Giannoudis et al .showed that ATF2 increases the transcription of genes such as MMP13, cyclin A, aromatase, and MMP2, which can contribute to breast cancer metastasis and pr olifer ation.The incr eased tr anscription of MMP13 by AFT2 may play a role in facilitating the metastasis of breast cancer to bone.For cyclin A, it has been found that its transcription is led primarily by cJun-ATF2 dimers increasing cell proliferation. 21Evidence of increased aromatase transcription by ATF2 was shown in a study that concluded that there were increased quantities of phosphorylated A TF2 ( pA TF2 ) at the promoter of the aromatase gene responsible for estrogen synthesis after co-culturing with malignant epithelial cells in primary human adipose fibroblasts obtained fr om br east cancer patients. 39ATF2 is also thought to play a major role in breast cancer metastasis, as its phosphorylation ( pATF2 ) has been demonstrated to enhance the transcription of MMP2, which boosts migration in HRas-transformed MCF10A human breast epithelial cells. 40ATF2 also combines with c Jun and c-Fos to facilitate HER2 activation of cyclooxygenase-2 ( COX2 ) , which is implicated in the growth and metastasis of cancer. 41Numer ous r esearc h studies hav e indicated that v-src triggers the binding of ATF2 and CREB to the CRE/ATF site of the cyclin D1 gene, whic h r esults in the tr anscription of cyclin D1 in human breast cancer cells ( MCF7 ) . 21Furthermore, ATF2 potentially participates in pp60v-src signaling, a proto-oncogene that was found to accelerate the G1 phase pr ogr ession of the cell c ycle b y inducing cyclin D1 pr otein le v els in NIH3T3 cells . 42T hese collective findings str ongl y suggest that ATF2 plays a crucial role as an oncogene in breast cancer.
Another study investigated the effect of noxin on the ATF2 signaling pathway and its effect on breast cancer development. 43oxin, which is also known as c hr omosome 11 open reading frame 82 or DNA damage-induced apoptosis suppressor, is linked to pr e v enting cell death and pr omoting cell gr owth when the body is under stress.Ho w ever, the exact role of noxin in regulating cell growth is still a subject of debate, and ther e hav e been no reports on its function and association with breast cancer.In this r esearc h, it was discov er ed that high noxin expression was linked to advanced tumor, lymph node metastasis, and poor ov er all survi val of patients.No xin was found to hav e incr eased le v els of expr ession in br east cancer cells compar ed to normal breast cells.Noxin ov er expr ession boosted tumor pr olifer ation and maximized colony formation in MCF7 cells, while its depletion resulted in the opposite outcomes in MDA-MB-468 cells.Similarl y, pr olifer ation experiments sho w ed that noxin boosted the gro wth of normal breast cells, and further testing r e v ealed that cyclin D1 and cyclin E1 in MCF7 cells were upregulated when noxin was overexpr essed but downr egulated in MDA-MB-468 cells when noxin was depleted.Mor eov er, ov er expr ession of noxin also increased the le v els of phosphorylated p38 and ATF2 and lo w ered them when noxin le v els wer e r educed.Inhibiting p38 counter ed the effects of noxin ov er expr ession on cyclin D1, cyclin E1, and cell growth.Ov er all, the r esearc h indicated that noxin's role in worsening the outcomes of breast cancer was mainl y thr ough activ ating the p38-ATF2 pathway.As was evident in this study, inhibiting the p38-ATF2 pathway r e v ersed the unfavor able outcomes of noxin on br east cancer cells, whic h may pr ovide gr eat insight into the dev elopment of ne w drugs that alter the outcomes of breast cancer.In contrast, another study indicated that noxin acts as a negativ e r egulator of the p38-ATF2 pathway. 44It also indicates that the p38-ATF2 pathway may act as an a poptotic mec hanism in breast cancer.Silencing of NOX caused apoptosis of non-small cell lung carcinoma A549 cells by activating the p38-ATF2 pathwa y.T hese contr adictory r oles of ATF2 may indicate that it has dual r oles depending on the type of tumor and other factors affecting the tumor.Ther efor e, extensiv e r esearc h still needs to be done in this area.
A study by Tsai et al .experimented with the effect of timosaponin AIII on triple negative breast cancer cells ( TNBC ) .It also experimented with the mechanism by which it can bring about its effect.The work found that TAIII caused a dose-dependent inhibition of hepatocyte growth factor-induced invasion activity in TNBC.This inhibition is belie v ed to be accomplished through the activation of the ERK pathway, which in turn suppresses the nuclear expression of the ATF2 and COX genes .T his has also been linked to the reduction in the activity le v els of tr anscription factors such as AP-1, C/EBP, and CREB. 45Finally, Ha yaka wa et al .investigated the role of ATF2 in determining the c hemor esistance of breast cancer cells to DNA-damaging agents such as cisplatin, actinomycin D, methionine-S-methyl sulfonium chloride , and etoposide . 46T he study suggests that JNK leads to a drug resistance phenotype by activating ATF2, which plays an important role in mediating augmented DNA repair through a p53-independent mechanism.The article implies that the four DNA-dama ging a gents activ ate JNK, p38, and extr acellular signal-r egulated kinase ( ERK ) , ther eby incr easing phosphorylation and ATF2-dependent transcriptional activity in human breast cancer BT474 cells.ATF2 can r egulate numer ous component genes that contain functional AP-1 and/or ATF/CREB binding sequences.This multicomponent system likely plays an important role in the complex cellular response of DNA damage repair. 46The results of this study indicate that ATF2 can cause resistance to DNA-dama ging a gents by stim ulating DNA r epair and mediating a c hemother a peutic drug r esistance mec hanism.This study also pr ovides gr eat insight into the r ole of ATF2 in endocrine tr eatment and drug resistance in human breast cancer cells, which may provide an important basis for other r esearc h to de v elop effectiv e ther a peutic solutions to treat drug-resistant cancers.
As e vident fr om the studies performed, the exact r ole of ATF2 in the de v elopment of cancer is yet to be full y understood.Ther e ar e contr adictions r egarding the exact r ole of ATF2, as some research suggests that it may have a dual role depending on the type of cancer and other affecting factors .T her efor e, man y clinical trials are being performed to further investigate this topic.Research in this area might provide great insight into potential ther a peutic drugs that can target those pathways and help in the treatment of breast cancer.We performed a thorough search on clinicaltrials .gov, whic h yielded numer ous clinical trials in pr ogr ess/completed to test the impact of certain drugs on ATF2 pathways in the treatment of different types of cancers.Two clinical trials that focus on breast cancer specifically are discussed below.
One such study is from clinicaltrials .gov. 47 As explained abo ve , ATF2 is a transcription factor that plays major roles in regulating cell gr owth, differ entiation, and a poptosis.Dysr egulation of the MAPK-ATF2 signaling pathway has been linked with various diseases, including breast cancer.This clinical trial aims to investigate the efficiency of a combination ther a py of fulv estr ant and selumetinib in treating patients with advanced breast cancer that pr ogr essed after aromatase inhibitor therapy.Fulvestrant mainly bloc ks estr ogen r eceptors, while selumetinib inhibits the MAPK pathway, whic h can r esult in the activ ation of ATF2.The study investigates whether the addition of selumetinib to fulvestrant can enhance pr ogr ession-fr ee surviv al compar ed to fulv estr ant alone by targeting the MAPK-ATF2 signaling pathwa y.T he primary endpoint of the study was pr ogr ession-fr ee surviv al at 6 months.Secondary endpoints include ov er all surviv al, objectiv e r esponse r ate, and safety of the drug.The study enrolled ∼144 participants and was completed in 2022.The results sho w ed that the combination of selumetinib and fulv estr ant had worse efficacy parameters and pr ogr ession-fr ee surviv al than fulv estr ant with placebo.T he o v er all surviv al of patients did not show a significant difference between the study groups .T he combination drug was also not tolerable for many patients, which caused an early reduction in the dose of the treatment or discontinuity of the treatment for some patients.One suggested hypothesis explaining the negative results of the combination therapy is that the inhibition of the MAPK pathway causes a shift and an increase in the other cellular pathwa ys , such as the phosphatidylinositol 3-kinase pathwa y. 48T his pathwa y is one of the most activated pathwa ys in breast cancer and is believed to play a major role in endocrine resistance. 48nother study is "TAS-116 plus palbociclib in breast and Rbnull cancer", which is a preclinical phase 1 study investigating the combination ther a py of heat shock protein 90 ( Hsp90 ) inhibitor TAS-116 and cyclin-dependent kinase 4/6 inhibitor palbociclib in the treatment of breast cancer and retinoblastoma-null cancer ( Clinical trial-NCT05655598 ) .TAS-116 is an inhibitor of the Hsp90 c ha per one pr otein.This pr otein is involv ed in the activation of numerous oncogenic proteins, such as ATF2.The inhibition of Hsp90 is emerging as a promising therapeutic solution for cancer tr eatment; thus, ther e is a focus on Hsp90 inhibitors in se v er al curr ent clinical trials.P albociclib is a selective inhibitor of CDK4/6 ( kinases that play vital roles in the regulation of the cell cycle ) .It has pr ov en efficiency in the treatment of hormone rece ptor-positi ve breast cancer.T herefore , it is approved for use in combination hormone ther a py in this clinical trial.Investigating the possible synergy between TAS-116 and palbociclib in pr e v enting the growth and survival of breast cancer and Rb-null cancer cells and enhancing their outcomes is the main aim of this study.The results of this study and similar studies may provide substantial insight into potential ther a peutic str ategies by tar geting the Hsp90-ATF2 and CDK4/6 pathways in breast cancers.
The recent research findings presented in this review provide valuable insights into the evolving landscape of ATF2, particularly in the context of hormone-rece ptor-positi ve breast cancer and the intricate mechanisms involved in resistance and response to therapy.These studies collectively underscore the significance of novel substances targeting resistance pathways such as PI3K/AKT/mTOR ( mammalian target of rapamycin ) and CDK4/6, as well as the potential of mTOR and CDK4/6 inhibitors in r esha ping the standard of endocrine tr eatment. 8Additionall y, they shed light on the crucial role of ATF2 in endocrine resistance by modulating estr ogen r eceptor expr ession and activity, underscoring the importance of understanding the molecular underpinnings of resistance mechanisms . 21Furthermore , the research elucidates the complex signaling mechanisms involved in MMP-3 expression in response to IL-1 β, highlighting the significance of ATF-2 and ERK1 in this process. 29In the context of extra-terminal motif inhibitors ( BETi ) , one study demonstrates their activation of ATF2 through the JNK1/2 pathway, with ATF2 playing a dual role in attenuating the anti-tumor effects of BETi by modulating ferr optosis and incr easing nuclear factor erythr oid 2-r elated factor 2 ( NRF2 ) expression.This finding suggests a novel therapeutic strategy that involv es tar geting ATF2 or NRF2 in combination with BETi to impr ov e cancer tr eatment outcomes. 49Mor eov er, the study on microRNAs highlights their role in regulating Ras Suppressor Protein 1 and PINCH1, further underscoring the complexity of the molecular pathwa ys in volved in adhesion and survival signaling in breast cancer.Understanding the intricate interplay between MicroRNAs and these k e y proteins is essential for advancing our knowledge of breast cancer pathophysiology. 50Together, these recent findings have the potential to driv e innov ations in br east cancer treatment and contribute to more effective and targeted therapies.

Role of ATF2 in endocrine treatment of breast cancer
In a study, it was discov er ed that pATF2 is a r eliable pr edictor of prognosis and overall survival in patients with ER-positive breast cancer who were subjected to tamoxifen treatment. 20Furthermore, when ATF2 was silenced, the growth-inhibitory effects of tamoxifen were reduced in the tamo xifen-sensiti ve, ER-positi ve MCF7 cell line.Tamoxifen ther a py also caused ATF2 to be phosphorylated in its activation domain in a dose-dependent manner, whic h incr eased its tr anscriptional activity.These r esults suggested that ATF2 may play a tumor-suppr essiv e r ole in ER-positiv e breast cancer. 20Similarly, ATF2 has been reported to have both oncogenic and tumor-suppr essiv e pr operties in skin carcinogenesis, demonstr ating its a ppar ent dual r ole . 51,52T her efor e, a study was conducted to study the role of ATF2 in resistance to endocrine treatment. 21This study used an in vitro model of breast cancer and pr oduced inter esting findings.It basicall y tested the knoc kdown of ATF2 and its effect on two main cell types, MCF7 and TAMR cells.The latter have higher HER-2 protein levels and better ERK1/2 activity than the former.A more important difference is that TAMR cells were tamoxifen resistant, unlike MCF7 cells.Other variants of MCF7 cells that were also tamoxifen-r esistant, suc h as LCC2 and LCC9 cells, were also tested.The results sho w ed that when ATF2 was silenced, the growth of MCF7 parental cells was not affected.Ho w e v er, ther e was a substantial decrease in the growth of TAMR, LCC2, and LCC9 cells.Additionally, silencing ATF2 inhibited the migration and colony formation of TAMR, LCC2, and LCC9 cells.Knocking down ATF2 increased the levels of estrogen r eceptor ( ER ) and ER-r egulated genes in TAMR cells compared to MCF7 cells .T he R target genes that wer e mainl y affected wer e TFF1, GREB1, NCOA3, and PGR.Furthermore, differential pathway analysis confirmed that knocking down ATF2 increased ER activity in TAMR cells.Gene expr ession anal ysis also r e v ealed that se veral genes known to cause tamoxifen r esistance wer e differ entiall y r egulated by A TF2 in T AMR cells compar ed to par ental MCF7 cells .T hese results ma y suggest that ATF2 targets pathways associated with tamoxifen resistance .T hese findings also suggest that inhibiting ATF2 may be a way to overcome endocrine resistance and demonstrate the dual role of this transcription factor in regulating both endocrine sensitivity and resistance by modulating ER expression and activity. 21

Conclusion
In this r e vie w, we explor ed the topic of ATF2 and its role in the development of breast cancer.It is evident that the expression and phosphorylation of ATF2 is necessary for numerous cellular functions, such as cell growth, proliferation, inflammation, death, and DNA damage and repair.The phosphorylation and regulation of ATF2 is also accomplished through various signaling pathwa ys , r esidues, and pr otein kinases.Ther e is still uncertainty regarding the exact role of ATF2 in the development and outcome of br east cancer.Se v er al studies suggest that ATF2 may function as an oncogene, worsening the outcome of the disease, as it increases the transcription of genes such as MMP2, MMP13, cyclin A, and aromatase that contribute to the progression and metastasis of breast cancer.Other research has found that the expression of ATF2 plays a role in improving the outcome of breast cancer.It has been identified as a predictor of impro ved o verall survival in patients with certain types of breast cancer in the presence of tamoxifen tr eatment.Ov er all, we belie v e that mor e r esearc h needs to be done on this topic using the resources and claims we mentioned as bases for upcoming adv ancements.Pr ogr ess needs to be made to clarify the uncertainty surrounding the exact role of ATF2 and its different behaviors and outcomes in different types of cancers.
In conclusion, our r e vie w has r e v ealed se v er al k e y insights, including that ATF2 may have dual functions in the de v elopment of breast cancer.These findings have important implications for the de v elopment of ther a peutic drugs that tar get the pathways involved in the progression of the disease .T hrough our review, we hav e identified se v er al ar eas for further r esearc h, suc h as the exact role of ATF2 in endocrine resistance and the pathways that may be susceptible to endocrine tr eatment.Ov er all, this r e vie w highlights the significance of ATF2 at the molecular le v el in breast cancer pr ogr ession and underscor es the need for continued investigation in this area.As we have shown, se v er al clinical trials are ongoing in this regard that may yield very promising results for the ther a peutic tr eatment of br east cancer.

Figure 1 .
Figure 1.An illustration showing the ERK1/ATF2 pathway that upregulates MMP3 leading to several cellular effects.TF, transcription factors.

Figure 2 .
Figure 2.An illustration depicting the phosphorylation of ATF2 activation domains by phosphorylating factors and the consequent actions of ATF2 on gene transcription.p38, p38 MAPK.

Figure 3 .
Figure 3.An illustration showing how the JIP complex is activated by stress signalling molecules ( including ASK1, MAP2k7, and JNK ) , inducing the activation of ATF2 and C-JUN, which was shown to increase cellular mechanisms like chemoresistance, cell growth, and multiplication, which may enhance tumor pr ogr ession.JIP, JNK-inter acting pr otein; MAP2k7, mitogen-activ ated pr otein kinase; ASK1, a poptosis signal-r egulating kinase 1.

Table 1 .
Role of ATF2 in tumorigenesis of human cancers.